The invention disclosed herein concerns a process of making 2-aryl carbapenems. Carbapenem antibiotics, particularly thienamycin and imipenem (see U.S. Pat. Nos. 3,950,377 and 4,194,047) are well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections. Active 2-Aryl substituted Carbapenem include those disclosed in U.S. Pat. Nos. 5,034,384 and 5,011,832.
As is generally appreciated by those with skill in the art, the Carbapenem nucleus is unstable, thus necessitating mild coupling reagents. The present methods of coupling utilize toxic reagents. For example, one alternative procedure utilizes highly toxic stannane reagents. The stannane procedure also introduces toxic impurities which made purification of the product and subsequent processing difficult.
Processes disclosed in the prior art include the following:
Coupling to produce 2-aryl carbapenems was previously performed via stannane chemistry (Rano et al. Tetrahedron Letters 1990, 2853). Related couplings with .beta.-lactam containing substrates are given by Monroe and McDonald (Journal of Organic Chemistry 1989, 54, 5828), Kant (Tetrahedron Letters 1990, 3389), and Farina (Tetrahedron Letters 1988, 5739, 6043). Boronic acid or ester couplings were reported by Snieckus (Tetrahedron Letters 1990, 1665), Suzuki (Chem. Letters 1989, 1405; Journal of the American Chemical Society 1985, 107, 972).
In sharp contrast, the boronic acid coupling methodology disclosed herein present mild conditions, low toxicity and ease of product purification.
Selected examples of the generalized palladium catalyzed coupling of organometallic agents with enol triflates are reported by Scott and McMurry (Accounts of Chemical Research, 1988, 21,47), Stille (Agnew. Chem International Edition English, 1986, 25, 508) and Piers (Tetrahedron Letters 1991, 4555).